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Adam Bisaga, M.D.
Professor of Psychiatry
Columbia University Medical Center, New York, NY
Implementing Antagonist-
Based Relapse Prevention
Treatment for Buprenorphine-
Treated Individuals
Adam Bisaga, MD, Disclosures
• I receive support from NIDA and the State of
New York to conduct research and teaching
• No money received from drug companies
The contents of this activity may include discussion of off label or investigative drug uses. The
faculty is aware that is their responsibility to disclose this information.
2
Planning Committee, Disclosures
AAAP aims to provide educational information that is balanced, independent, objective and free of bias
and based on evidence. In order to resolve any identified Conflicts of Interest, disclosure information from
all planners, faculty and anyone in the position to control content is provided during the planning process
to ensure resolution of any identified conflicts. This disclosure information is listed below:
The following developers and planning committee members have reported that they have no
commercial relationships relevant to the content of this module to disclose: PCSSMAT lead
contributors Maria Sullivan, MD, PhD, Adam Bisaga, MD; AAAP CME/CPD Committee Members
Dean Krahn, MD, Kevin Sevarino, MD, PhD, Tim Fong, MD, Robert Milin, MD, Tom Kosten, MD, Joji
Suzuki, MD; and AAAP Staff Kathryn Cates-Wessel, Miriam Giles and Blair-Victoria Dutra.
Frances Levin, MD is a consultant for GW Pharmaceuticals and receives study medication from US
Worldmed. This activity’s planning committee has determined that Dr. Levin’s disclosure information
poses no bias or conflict to this presentation.
All faculty have been advised that any recommendations involving clinical medicine must be based on evidence that is
accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of
patients. All scientific research referred to, reported, or used in the presentation must conform to the generally accepted
standards of experimental design, data collection, and analysis. Speakers must inform the learners if their presentation will
include discussion of unlabeled/investigational use of commercial products.
3
Educational Objectives
• At the conclusion of this activity participants
should be able to: Describe the evolution of antagonist-based treatment for opioid
dependence
State guidelines to select most appropriate patients for treatment
with naltrexone
Determine pharmacological strategies to initiate treatment with
naltrexone
Identify clinical challenges encountered during treatment with
naltrexone
Implement naltrexone in addiction practice competently
4
5
Target Audience
• The overarching goal of PCSS-MAT is to make
available the most effective medication-assisted
treatments to serve patients in a variety of settings,
including primary care, psychiatric care, and pain
management settings.
6
Accreditation Statement
• American Academy of Addiction Psychiatry (AAAP)
is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing
medical education for physicians.
7
Designation Statement
• American Academy of Addiction Psychiatry
designates this enduring material educational
activity for a maximum of 1 (one) AMA PRA
Category 1 Credit™. Physicians should only claim
credit commensurate with the extent of their
participation in the activity.
Date of Release: April 1, 2014
Date of Expiration: April 1, 2016
Participation in this CME Activity
• In order to complete this online module you will need
Adobe Reader. To install for free click the link below:
http://get.adobe.com/reader/
• You will need to complete a Post Test. You will then be
directed to a module evaluation, upon completion of
which you will receive your CME Credit Certificate or
Certificate of Completion via email.
8
Receiving your CME Credit or
Certificate of Completion
Upon completion of the Post Test:
• If you pass the Post Test with a grade of 80% or higher, you will be instructed to click a link which
will bring you to the Online Module Evaluation Survey. Upon completion of the Online Module
Evaluation Survey, you will receive a CME Credit Certificate or Certificate of Completion via email.
• If you received a grade lower than 79% on the Post Test, you will be instructed to review the Online
Module once more and retake the Post Test. You will then be instructed to click a link which will
bring you to the Online Module Evaluation Survey. Upon completion of the Online Module
Evaluation Survey, you will receive a CME Credit Certificate or Certificate of Completion via email.
• After successfully completing the Post Test, you will receive an email detailing correct answers,
explanations and references for each question of the Post Test.
9
Outline
• Agonist vs. antagonist-based treatment of opioid dependence
• Early experiences with opiate blockers
• Strategies to improve effectiveness of naltrexone
Long-acting preparation
• Selection of candidates for naltrexone
• Methods for initiating treatment with naltrexone
Naltrexone induction algorithms
Adjunctive medications
Managing ‘naltrexone flu’
• Clinical challenges and controversies with naltrexone treatment
Testing the blockade
Concerns about overdose risk
10
Opioid Dependence Treatment Goals
• Help patients to stop using opiates
• Provide protection against the risk of overdose
and death
• Teach skills necessary to cope with cravings and
life stressors without drugs
• Medications, most likely given over an extended
period of time, perhaps indefinitely, should be the
mainstay of opioid dependence treatment
• Treatment should be focused on recovery, and
many ways it could be reached
11
The Role of Medication in Treatment
of Opioid Dependence
• Detoxification from opioids without pharmacological support afterwards remains the dominant model of treatment
Despite decades of experience and evidence to the contrary
• Medications to prevent relapse are not routinely offered after detoxification
Result of an emphasis on being opiate- (medication-) free as the treatment goal rather than on the treatment as protection against negative consequences
• First weeks following detoxification are the most dangerous phases of opioid dependence, with a significant risk of overdose and death
Pharmacological assistance to prevent overdose is essential during this period
It is imperative that either agonist or antagonist is offered to individuals who want to stop using opiates
Individuals who decide to undergo detoxification are in an ideal position to have a trial of antagonist to prevent relapse
12
Choosing Agonist vs.
Antagonist Based Treatment
AGONIST ANTAGONIST
Maintain physiological dependence and
potential for withdrawal + -
Potential for tolerance development +/- -
Euphoric effects/abuse/diversion ++ -
Compatible with ongoing illicit opioid use ++ -
May alter use of other drugs +/- ++
Extinction of heroin-reinforced
behaviors/reversal of underlying neurobiology + ++
Duration of treatment Indefinite? ?
Cultural/ideological barriers to availability ++ -
Professional/public opposition ++ +
Not offering medication after they stop drug use
puts patients at increased risk of overdose and death 13
Using Blockers to Treat
Opiate Dependence • The concept developed in parallel to methadone, in part
fueled by the controversies in response to methadone
• In 1960s studies by Martin on various opiates in humans discovered opiate blockers, naltrexone was well tolerated and had a long duration of action
Subjects maintained on the blocker did not feel effects of morphine and it was impossible to induce physical dependence
• Wikler suggested that opiate blockers are used for treatment of heroin addiction
Based on the behavioral/learning model of addiction, attempts at re-addiction while on the blocker will lead to the extinction of drug seeking
14
Why There Are Very Few
Patients on Naltrexone• When heroin epidemic reached panic proportions in 1970s,
NIDA had a very active portfolio of naltrexone grants (21 grants 1973-74)
• Results of first years of studies with oral preparations were disappointing
Low patient acceptability and poor compliance
It became clear that to have more patients benefit from naltrexone, better methods of induction and long-term maintenance needed to be developed
• Meta-analytic studies (e.g., Cochrane Review) concluded that studies to adequately assess the effectiveness of oral naltrexone are lacking which might have discouraged its clinical use
15
Improving Effectiveness of
Naltrexone (1980s - )
• Development of novel methods of detoxification
Clonidine become available to treat withdrawal (Gold et al., 1978)
Rapid Detox: detoxification was accelerated by administering antagonist
and emerging symptoms are treated with clonidine (Riordan & Kleber
1980)
General anesthesia and an Ultra-Rapid Detox (1-day detox) was
introduced (Loimer 1988)
Buprenorphine was introduced as a step-down from methadone during
detoxification (Kosten et al., 1992)
• Using antagonists during detox became an opportunity to start naltrexone
as a relapse prevention agent: Rapid Naltrexone Induction (Brewer)
• Work continued on improving adherence to oral preparations using
tailored behavioral therapy (BNT: Sullivan et al., 2006)
• Several long-acting preparations of naltrexone become available to deal
with compliance issue
16
Improving Treatment Retention
Using Long-Acting Preparations
• Injections
1st gen: oil suspension
(Wedgewood)
2nd gen: microspheres
with NTX in suspension
Vivitrol licensed in 2007
• Implants
1st gen: compressed NTX
c. 1996, now licensed in
Russia (Prodetoxone)
2nd gen: NTX mixed with
polymer matrix c.2001,
Australia)
17
Efficacy of Extended-Release
(XR) Naltrexone
• In research studies comparing oral vs. XR (injections, implants) naltrexone, treatment retention rate in the XR group is twice that of the oral group, approximating 50-70% at 6 months (Hulse et al., 2009; Krupitsky et al., 2012, Kunoe et al., 2009; Brooks et al., 2011)
• Blinded trials comparing injectable naltrexone with injection of placebo show that patients receiving active naltrexone are successful in treatment, and this effect is dose related (Comer et al., 2006; Krupitsky et al., 2011)
18
Selection of Candidates for Naltrexone
• Patients who are not interested or able to be on agonist maintenance
Those with high degree of motivation for abstinence (active in 12-step programs)
In professions where treatment with agonist is controversial (healthcare professionals, pilots)
• Patients successful on agonist but who want to try abstinence
• Patients who failed prior treatment with agonist
Continued use of heroin, did not improve/dropped out
• Patients who are abstinent but at risk for relapse
Moving to old neighborhood, increased stress, worsening psychiatric problems
• Patients for whom relapse would be disastrous (e.g., physicians, pilots, parolees)
19
Selection of Candidates for Naltrexone (continued)
• Patients with less severe form of a disorder
Short history of use, lower level of use
• Who is most likely to benefit from naltrexone?
Highly motivated patients who are committed to
abstinence
Older patients with long history of use and
multiple relapses
Those with longer periods of abstinence
between relapses
Patients who relapsed and returned to treatment
do better
20
Patients Who are Better Candidates
for Agonists
• Patients with history of overdoses, particularly following detoxification
• Patients with serious mental illness, disorganized, homeless
• Patients who have been opiate-free but never felt “normal”
Patients in whom psychiatric illness emerged/worsened after previous detoxes (with or w/o naltrexone)
• Patients with chronic pain requiring chronic opioid treatment
• Patients with severe GI disorders exacerbating during withdrawal/abstinence
• Patients with advanced liver disease (Brewer and Wong, 2004)
Concerns about hepatotoxicity are not based on the representative data
Naltrexone is used for treatment of pruritus in jaundiced patients with severe liver disease
21
Initiating Naltrexone
• No single best method but rather a set of approaches/tools that can be
individualized to individual patient and the treatment team (experience)
• Ability of the team to expect and respond to emerging complications, to
maintain enthusiasm and confidence in the method can influence outcome
• Effective method will balance the degree of discomfort and the duration of
treatment
22
Naltrexone Initiation During Detoxification:
Rapid Naltrexone Induction Procedure
• Approximately 70% of patients complete inpatient rapid naltrexone induction procedure and accept long-acting naltrexone (NTX-XR)
• Modification of the algorithm depending on the level of physiological
dependence
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Buprenorphine admission 4 mg bid
Naltrexone 3 mg 6 mg 25 mg 50 mg po
380 mg im
Supportive
medications
clonidine 0.1-0.2 mg qid, clonazepam 0.5-1.0 mg qid,
toradol, ranitidine, zolpidem, trazodone
Columbia Rapid NaItrexone Induction Protocol
23
Rapid Naltrexone Induction Algorithm (Sigmon et al., 2012)
Severity (physical dependence/anticipated withdrawal)
NONE Already abstinent (completed
buprenorpine taper and has
abstained for 7-10 days, exiting
controlled environment)
MILD H: 1-2 bags/day; OXY: <50mg/day
Setting Outpatient Outpatient or partial hospital
Buprenorphine Dose None None or 4mg, day 1
Clonidine None 0.1-0.2 mg TID to QID
Clonazepam None 0.5 mg BID
Ancillary medications None Sleep, pain (e.g. NSAID)
Hydration Routine Aggressive oral hydration (e.g.,
sports drinks)
Time to first NTX dose Day 1 Day 3
Initial oral NTX dose 25-50 mg 12.5 mg QD
Time to Vivitrol
injection
Days 1-2 Day 4; (or Day 5-6 after titrating oral
naltrexone to 25-50mg QD)
24
Rapid Naltrexone Induction Algorithm (continued)
Severity (physical dependence/anticipated withdrawal)
MODERATE H: 3-6 bags/day; OXY (50-
100mg/day); following short-term
methadone or buprenorphine taper
SEVERE > 6 bags/day; illicit methadone; severe
prescription opioid use (>100 mg/day);
significant medical problems
Setting Partial hospital with with
inpatient backup
Inpatient or partial hospital with
inpatient backup
Buprenorphine Dose 4-8 mg, day 1 or 2 8 mg, day 1 or 2, or >8 mg as
needed
Clonidine 0.2 mg (TID to QID) 0.2-0.3 mg QID
Clonazepam 1.0-2.0 mg (TID to QID) 1.0-2.0 mg QID
Ancillary medications Sleep, pain, GI distress Sleep, pain, GI distress
Hydration Aggressive oral hydration Aggressive oral or IV hydration
Time to first NTX dose Days 3-4 Day 4-5 (later if needed)
Initial oral NTX dose 6 mg BID 3-6 mg QD-BID
Time to Vivitrol
injection
Days 4-5; or days 5-7 after
titrating oral naltrexone to 25-
50 mg QD)
Day 5-6; (or Day 6-7 after titrating
oral naltrexone to 25-50mg QD)
25
Adjunctive Medication Used During Detox/NTX Induction
Symptoms Drug Class Medication (dosage)
Autonomic arousal
(sympathetic)
Α2-adrenergic agonists • Clonidine (0.1–0.3 mg PO q 6–8 h)
• Lofexidine (0.6–2 mg/d in 2–3 div doses)
Anxiety/restlessness Benzodiazepines
Antihistamines
• Clonazepam (0.5–2 mg PO q 4–8 h)
• Oxazepam (15–30 mg PO q 4–6 h)
• Lorazepam if parenteral (IM, IV) dosing needed
• Diphenhydramine (50–100 mg PO q 4–6 h)
• Hydroxyzine (100–150 mg PO q 6 h)
Insomnia Sedating antidepressants
Non-benzodiazepine hypnotics
Sedating atypical neuroleptics
• Trazodone (50–150 mg PO at hs)
• Doxepin (50–100 mg at hs)
• Zolpidem (10 mg PO at hs)
• Eszopiclone (3 mg PO at hs)
• Quetiapine (50–200 mg PO at hs)
Musculoskeletal
pain
NSAIDs
Aniline analgesics
Antispasmodics
• Ibuprofen (400 mg PO q 4–6 h)
• Aspirin (650 mg PO q 4–6 h, max 4 g/d)
• Ketorolac (30 mg IM q 6 h, max 120 mg/d for 5d)
• Acetaminophen (650–1000 mg PO q 4–6 h)
• Cyclobenzaprine (5–10 mg PO q 4–6 h); others
include baclofen, tizanide, methocarbamol)
GI Distress (nausea,
vomiting, diarrhea)
Oral hydration
Antiemetics
5HT3 antagonist
Miscellaneous
• Sports drinks (contain electrolytes), diluted fruit
juice, bouillon
• IV fluids as backup if needed
• Prochlorperazine (5–10 mg PO or IM q 3–4 h)
• Promethazine (25 mg PO or IM q 4–6 h)
• Ondansetron (8–16 mg PO or IM q 8–12 h)
• Bismuth subsalicylate (2 tablets PO q 1 h)
• Loperamide (2 mg PO after each BM
26
Transition from Buprenorphine
Maintenance to Naltrexone
• Many people who are unable to taper off buprenorphine have anxiety disorder, which can benefit from SSRI or an anticonvulsant (gabapentin, pregabalin)
• People who stop buprenorphine maintenance are either anxious or
sedated, treat symptomatically accordingly (e.g., clonazepam, stimulant)
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Buprenorphine 2 mg qd
Naltrexone 1-3 mg 6 mg 25 mg
50 mg po
380 mg
im
Supportive
medications
clonidine 0.1-0.2 mg qid, clonazepam 0.5-1.0 mg qid,
toradol, ranitidine, zolpidem, trazodone, d-amphetamine
27
Protracted Withdrawal: Naltrexone Flu
• Patients who start naltrexone right after detoxification commonly
experience a “flu-like” sign and symptoms
Somatic complaints: insomnia, GI distress, hyperalgesia, anergia
Anxiety, irritability, dysphoria, anhedonia
Severity may be lower if naltrexone is started 10-14 days after completion of
detoxification (but many relapse by then)
• Partially alleviated with aggressive symptomatic treatment,
Insomnia (v. frequent, often severe): zolpidem, trazodone, quetiapine
GI distress: H2 blockers
Anxiety/hyperarousal: clonazepam, clonidine
• Most of these symptoms remit by 2-4 weeks
True prolonged symptoms are rare and likely reflect additional psychopathology
• Persistent/protracted withdrawal vs. acute effects of naltrexone (?)
Negative mood and vegetative symptoms are significantly higher in participants
who are receiving higher dose of naltrexone
28
Clinical Challenges:
Testing the Blockade • It is expected that approximately 50% of patients will ‘test’
blockade often same day as discharge
Make sure sufficient levels of naltrexone are present on discharge
(oral supplementation if NTX-XR is given on the day of discharge)
• Most commonly patients will test 1-3 times with low doses of
opioid during the first few days after discharge, after which they
are reassured blockade works and do not return to use
• Some patients will use large amounts, for 1-3 weeks, trying to
get high
• Very few patients will continue using, often IV, even though
they are blocked, but are interested staying on naltrexone
• Rarely, NTX is quickly metabolized, blood levels are low and
patients may become re-dependent while receiving NTX as
recommended
29
Clinical Challenges:
Managing Relapse
• Some patients have increased craving and may use in
weeks 3-4, in those more frequent injection or oral
supplementation is needed
• Most commonly, the first sign of relapse is missing
doses/injections. The blockade wears off 2-3 days after
oral and 5-6 weeks after injectable doses
Additional therapy, involving network members is useful to
improve adherence
Inpatient stabilization and another attempt at antagonist
treatment
Residential treatment/sober house
Transition onto agonist
30
Safety Concerns: Overdose
• Risk of overdose is significant if patient decides to stop taking
naltrexone, stop attending treatment and resumes opiate use
Provide detailed description of risks (signed consent for treatment),
continue discussing risks in patients who continue use:
Consider transition onto agonist to decrease risk of overdose if
unable to comply with NTX
• Fear of overdose applies to any completed detoxification or
discontinuation of agonist maintenance. Naltrexone,
especially long-acting, actually PROTECTS against overdose
“I understand that after I stop naltrexone I may be more sensitive to the effects of heroin
and any other narcotics. The amount of heroin or narcotics I may have been using on a
routine basis before I started naltrexone, might now cause overdose and death. I fully
understand the nature and seriousness of this possible consequence.
If I am not sure that I can avoid opiate use, I understand that I can be referred to
alternative treatment programs, such as a methadone maintenance, which is an effective
treatment for heroin dependence and has a reduced risk of fatal overdose.”
31
Managing Severe Pain
• First try full doses of NSAIDs (e.g., ketorolac injection)
• For persistent or intolerable pain try regional nerve blocks
• High potency opiates (fentanyl or buprenorphine) can override blockade but buprenorphine is safer, anesthesiology involvement is advisable
• Patients should wear medical bracelet or wallet
card with a 24-hr contact number
32
Controversies Surrounding Antagonist
Based Treatment Approaches
• Concerns about safety of this treatment: whether treatment with naltrexone increases risk of depression, suicidality, and overdose post-treatment
No convincing evidence that NTX may increase depression (not well studied)
There may be higher risk of an overdose compared to patients on agonist, but such risk is low, lower than in untreated individuals, and likely similar to risk in those who stop agonists
The long “tail” on the serum naltrexone curve with LA preparation may provide protection during early experience of the drug-free lifestyle, which was previously marked by an elevated mortality
• Concerns about inadequate efficacy (as compared to agonists)
Is naltrexone inferior to methadone/buprenorphine? On what outcomes (retention vs. continuing use), in what samples?
Recent studies with buprenorphine show comparable treatment retention and lower rates of opiate use
Controlled, direct comparison trials have not been done
33
Naltrexone in Clinical Practice
• Naltrexone can be offered to:
Patients coming out of rehab who can be easily started on
extended release preparation
Patients who had some abstinent time after detox/rehab but
struggle, have intense cravings, and started using, though are
not dependent yet (naloxone challenge needed)
Patients who requested brief buprenorphine taper and want to
be protected from relapse
Young patients with a brief episode of Rx opiate use and
involved parents
Patients who were stable on buprenorphine but would like not to
be dependent and take medication daily
34
Naltrexone in Clinical Practice (continued)
• Naltrexone complements treatment with
buprenorphine offered in private addictions
practice
Experienced buprenorphine providers should try
offering naltrexone, a lot of fears will dissipate
Treatment matching is more important than proving
superiority of any one method
35
Educational Objectives
• At the conclusion of this activity participants
should be able to: Describe the evolution of antagonist-based treatment for opioid
dependence
State guidelines to select most appropriate patients for treatment
with naltrexone
Determine pharmacological strategies to initiate treatment with
naltrexone
Identify clinical challenges encountered during treatment with
naltrexone
Implement naltrexone in addiction practice competently
36
37
Case Vignette
57 y.o. Male, Using 5 Bags of
Heroin Daily, Seeking Treatment
Adam Bisaga M.D.
Maria Sullivan M.D., Ph.D.
38
Case Presentation: History
• 57-year-old opioid-dependent male using 5 bags/day (IN)
• Using heroin regularly for 22 years
• Had a 5-year period of abstinence before relapsing 6 months earlier
• Patient is smoking marijuana daily and uses cocaine 2-3 times/month
• Patient seeks injectable naltrexone treatment as he is not interested in agonist maintenance
39
Presentation on Evaluation
• Physical examination: hypertension
• Psychiatric evaluation: substance-induced
mood disorder (depressed mood, moderate
anhedonia, decreased sleep)
• Urine toxicology: positive for heroin, cocaine,
and THC
40
Treatment: What can be offered?
• Polysubstance dependence is present, so patient cannot undertake treatment for opioid dependence without first addressing daily MJ use and cocaine abuse
• Presence of a mood disorder makes opioid dependence treatment unlikely to succeed; depression must be treated first
• Opioid dependence can be treated, despite depression and other concurrent substance dependence
41
How would you proceed at this
point?
1. Inpatient detoxification (1-2 days of buprenorphine, 3-4
days of washout) followed by naloxone challenge and
injection of XR-naltrexone
2. Outpatient detoxification over 7 days: rapid naltrexone
induction (1-day buprenorphine followed by increasing
doses of oral NTX, and administration of injectable
naltrexone)
3. Weeklong buprenorphine taper followed by a weeklong
washout, and then injectable naltrexone administration
4. Induction onto buprenorphine maintenance
5. Advise patient to abstain from using heroin for 14 days
and, once negative, to come in for injectable naltrexone
injection
42
Treatment Considerations
• Patient is unable to go inpatient due to
familial and occupational responsibilities
• Increased risk of resuming opioid use during
the washout week
• Patient does not want to be on
buprenorphine maintenance
• Patient has previously had a 5-year period of
sustained abstinence
43
Outpatient Induction onto injectable
naltrexone
• Patient presents in mild withdrawal after his last use of heroin (1 bag) 14 hours previously
• Administered 2 mg of buprenorphine, followed by a second 2mg dose 1 hour later
• Sent home with 4 mg of buprenorphine to take over the course of the evening
• Reported using methadone upon arriving home, followed by 4 mg of buprenorphine, causing the precipitation of opioid withdrawal
44
How would you proceed at
this point?
• Abandon outpatient induction and insist on
admission to inpatient unit for completion of
the naltrexone induction process
• Referral to agonist maintenance
• Continue with outpatient induction
procedure, adjusting regimen to clinical
presentation
45
Continuation of outpatient
naltrexone induction
• Buprenorphine washout was extended for
additional 2 days
• Higher doses of ancillary medications
(clonidine, clonazepam, prochlorperazine,
and zolpidem) were administered
• Daily monitoring, medication
dosing/adjustment was conducted at the
clinic
46
Response
• Reported moderate intensity symptoms of insomnia, anxiety, runny nose, and back pain
• The patient continued to receive ancillary medications and oral naltrexone induction was initiated
• Patient tolerated increased doses of oral naltrexone (Day 1: 1mg x 3; Day 2: 6mg x 2; Day 3: 25mg)
• Once the patient was able to tolerate 25mg oral naltrexone, injectable naltrexone was administered 1 hour later
• Was inducted onto injectable naltrexone but during the first week complained of severe insomnia; also anxiety, depression, and decreased appetite
47
Insomnia: Differential diagnosis
• Persisting/protracted opioid withdrawal
• Naltrexone-induced withdrawal syndrome
(“naltrexone flu”)
• Naltrexone-induced mood disorder
• Underlying mood/anxiety disorder that
reemerged during opioid abstinence
48
Acute Intervention: Goals
• Treatment retention; if we don’t treat distressing symptoms, he will not come back for another injection and likely will resume heroin use
• Regardless of the etiology, insomnia should be aggressively managed to maximize comfort and treatment engagement
• Patient was treated with zolpidem 10 mg/HS, trazodone 100 mg/HS and clonazepam 2 mg/d for two weeks post-injection
• Weekly psychotherapy aimed at developing strategies to deal with limited sleep and physical distress and motivating to remain in treatment and on medication
49
Patient Response/Outcome
• Patient reported no use of opioids, but continued to smoke marijuana daily
• Insomnia, mood, and decreased appetite improved and resolved by the 3rd week of treatment
• Accepted 2nd and 3rd injection of naltrexone, and has not used any opioids since the first day of induction
• Patient is interested in remaining on injectable naltrexone, for 1 year, as recommended
50
Case Discussion
• Patients using during the first week of induction are at
high risk of not completing procedure, and the protocol
needs to be flexible to accommodate them
• Once on the injectable naltrexone, as many as 50% of
patients will use opioids, but most will test the blockade
2-5 times and then stop
• Persisting with naltrexone induction can be effective in a
majority of cases to help patients enter stable abstinence
• During early opioid abstinence on XR-NTX, other
substance abuse may need to be tolerated initially; can
be addressed in behavioral therapy sessions
References
• Brewer C, Wong VS. 2004. Naltrexone: report of lack of hepatotoxicity in acute viral
hepatitis, with a review of the literature. Addict Biol 9:81-7.
• Brooks A, Sullivan MA, Comer SD, Bisaga A, Carpenter KM, Raby, Yu E, O’Brien, and
Nunes EV Long acting injectable versus oral naltrexone maintenance therapy with
psychosocial intervention for heroin dependence: A quasi-experiment. J Clin Psych,
2010:1371-8.
• Comer SD, Sullivan MA, Yu E, Rothenberg JL, Kleber HD, et al. 2006. Injectable,
sustained-release naltrexone for the treatment of opioid dependence: a randomized,
placebo-controlled trial. Arch Gen Psychiatry 63:210-8.
• Greenstein RA, Arndt IC, McLellan AT, O'Brien CP, Evans B. 1984. Naltrexone: a clinical
perspective. J Clin Psychiatry 45:25-8.
• Greenstein RA, Evans BD, McLellan AT, O'Brien CP. 1983. Predictors of favorable
outcome following naltrexone treatment. Drug Alcohol Depend 12:173-80.
51
References
• Hulse GK, Morris N, Arnold-Reed D, Tait RJ. 2009. Improving clinical outcomes in treating
heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen
Psychiatry 66:1108-15.
• Judson BA, Goldstein A. 1984. Naltrexone treatment of heroin addiction: one-year follow-
up. Drug Alcohol Depend 13:357-65.
• Kleber HD, Kosten TR. 1984. Naltrexone induction: psychologic and pharmacologic
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• Krupitsky, E., Zvartau, E., Blokhina, E., Verbitskaya, E., Wahlgren, V., Tsoy-Podosenin,
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Funding for this initiative was made possible (in part) by Providers’ Clinical Support System for Medication
Assisted Treatment (1U79TI024697) from SAMHSA. The views expressed in written conference materials or
publications and by speakers and moderators do not necessarily reflect the official policies of the Department of
Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply
endorsement by the U.S. Government.
PCSSMAT is a collaborative effort led by American Academy
of Addiction Psychiatry (AAAP) in partnership with: American
Osteopathic Academy of Addiction Medicine (AOAAM),
American Psychiatric Association (APA) and American Society
of Addiction Medicine (ASAM).
For More Information: www.pcssmat.org
Twitter: @PCSSProjects
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